A novel ErbB2 epitope targeted by human antitumor immunoagents
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Fulvia Troise1, Maria Monti, Antonello Merlino
1Dipartimento di Biologia Strutturale e Funzionale, Università di Napoli Federico II, Napoli, Italy.
Abstract:
Two novel human antitumor immunoconjugates, engineered by fusion of a single-chain antibody fragment against human ErbB2 receptor, termed Erbicin, with either a human RNase or the Fc region of a human IgG(1) , are selectively cytotoxic for ErbB2-positive cancer cells in vitro and in vivo. These Erbicin-derived immunoagents (EDIAs) do not show the most negative properties of Herceptin, the only humanized mAb against ErbB2 used in the therapy of breast carcinoma: cardiotoxicity and the inability to act on resistant tumors. These differences are probably attributable to the different ErbB2 epitopes recognized by EDIAs and Herceptin, respectively, as we have previously reported that they induce different signaling mechanisms that control tumor and cardiac cell viability. Thus, to accurately identify the novel epitope recognized by EDIAs, three independent and complementary methodologies were used. They gave coherent results, which are reported here: EDIAs bind to a different ErbB2 epitope than Herceptin and the other human/humanized antibodies against ErbB2 reported so far. The epitope has been successfully located in region 122-195 of extracellular domain I. These findings could lead to the identification of novel epitopes on ErbB2 that could be used as potential therapeutic targets to mitigate anti-ErbB2-associated cardiotoxicity and eventually overcome resistance.
Insights
Two new immunoconjugates, Erbicin-derived immunoagents (EDIAs), show selective cancer cell toxicity without Herceptin
Area of Science:
- Oncology
- Immunology
- Biotechnology
Background:
- Human antitumor immunoconjugates are engineered for targeted cancer therapy.
- Erbicin-derived immunoagents (EDIAs) are novel fusion proteins targeting the human ErbB2 receptor.
- Existing ErbB2-targeted therapies like Herceptin have limitations, including cardiotoxicity and resistance.
Purpose of the Study:
- To characterize the specific ErbB2 epitope recognized by EDIAs.
- To understand the differences in epitope binding compared to Herceptin and other ErbB2 antibodies.
- To identify novel therapeutic targets for improved anti-ErbB2 therapies.
Main Methods:
- Utilized three independent and complementary methodologies to identify the EDIA-binding epitope.
- Characterized the binding interactions of EDIAs with the human ErbB2 receptor.
- Compared the epitope recognized by EDIAs with those targeted by Herceptin and other ErbB2 antibodies.
Main Results:
- EDIAs bind to a distinct ErbB2 epitope compared to Herceptin and other human/humanized ErbB2 antibodies.
- The identified epitope is located within region 122-195 of the ErbB2 extracellular domain I.
- These findings provide a molecular basis for the differential therapeutic properties of EDIAs.
Conclusions:
- EDIAs recognize a novel epitope on the ErbB2 receptor.
- This novel epitope mapping offers potential for developing next-generation anti-ErbB2 therapies.
- Targeting this new epitope may mitigate cardiotoxicity and overcome resistance associated with current ErbB2 treatments.
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